Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay

doi:10.1016/j.bmc.2023.117477

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	Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay
	Shen,Meiling; Li,Lingfeng; Li,Yue; Gu,Xi; Bai,Longhui; Xia,Chengfeng; Xiong,Wenyong; Zuo,Zhili
	2023
发表期刊	BIOORGANIC & MEDICINAL CHEMISTRY
ISSN	1464-3391
卷号	94 页码:117477
摘要	The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca2+ into cells, thereby modulating cellular depolarization and intracellular ion concen-tration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (https://www.chemdiv.com) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca2+ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca2+ levels in hTRPC5-overexpressing HEK 293T cells, with IC50 values of 10.2 mu M and 10.3 mu M, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.
关键词	TRPC5 Inhibitors Virtual screening Ca 2+channel CHANNELS IDENTIFICATION PERMEABILITY CALCIUM
DOI	10.1016/j.bmc.2023.117477
收录类别	SCI
WOS记录号	WOS:001079364500001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75458
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Shen,Meiling,Li,Lingfeng,Li,Yue,et al. Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,94:117477.
APA	Shen,Meiling.,Li,Lingfeng.,Li,Yue.,Gu,Xi.,Bai,Longhui.,...&Zuo,Zhili.(2023).Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay.BIOORGANIC & MEDICINAL CHEMISTRY,94,117477.
MLA	Shen,Meiling,et al."Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay".BIOORGANIC & MEDICINAL CHEMISTRY 94(2023):117477.

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